DESCRIPTION: The induction of HIV-specific broadly reactive neutralizing antibodies by vaccination is the ultimate goal of the HIV vaccine field. There have been encouraging recent reports of the isolation of neutralizing antibodies from HIV-infected individuals. However, it is now clear that these antibodies require considerable somatic mutation to evolve into effective neutralizing antibodies. Induction of these neutralizing antibodies by vaccination, therefore, remains one of the key challenges of the field. In contrast to neutralizing antibodies, we already know how to induce HIV-specific CD8 T cells by vaccination. Furthermore, the T cell receptors (TCRs) expressed by these antigen-specific CD8 T cells do not require somatic mutation to be effective. It is generally thought that these vaccine-induced CD8 T cells might provide some measure of control of acute phase viral replication and then reduce viral replication in the chronic phase. Indeed, there is considerable evidence that this can be achieved in vaccinated rhesus macaques. Accumulating data also suggests that vaccine-induced CD8 T cells can prevent chronic phase replication of the AIDS virus. In this proposal, we will rigorously test the hypothesis that CD8 T cells can prevent chronic phase viral replication after infection with the AIDS virus. We will induce CD8 T cells using a new, innovative vaccine regimen consisting of a recombinant DNA prime, followed by a recombinant Yellow Fever boost to induce high frequency classical effector memory T (TEM) cell responses that will be focused on immunodominant epitopes. We will then maintain these responses with a final vaccination with a continually replicating recombinant Rhadinovirus. This vaccine regimen will induce and maintain high frequency TEM and we will determine whether these TEM CD8 T cells can control chronic phase viral replication after repeated low dose rectal challenge of Indian rhesus macaques. In this proposal we plan to carry out two specific aims. In specific aim one, we will vaccinate six Mamu-B*08 and six Mamu-B*17 positive macaques with small regions of Vif and Nef encoding Mamu-B*08- and Mamu- B*17-restricted epitopes and then challenge them with repeated low doses of SIVmac239. In our second aim, we will vaccinate six Mamu-A*01 and six Mamu-A*02 positive macaques with small regions of Gag, Tat and Nef and also challenge them with repeated low doses of SIVmac239. We already have preliminary evidence that this vaccine regimen is effective and can reduce viral replication after a high dose SIVmac239 challenge. Should this new vaccine regimen prevent chronic phase replication of SIV, this would open up an entirely new arena of HIV vaccine research.